As circumventricular organs, the subfornical organ (SFO), situated at the front of the brain, and the area postrema (AP), located at the rear of the brain, lack a blood-brain barrier making them putative central receptor sites for humoral factors affecting behavioral and physiological controls of homeostasis. Each has efferent neural projections enabling them to affect brain function. The SFO primarily affects preoptichypothalamic function and the AP primarily affects relays for ascending visceral afferent information. The first major objective of this grant is to determine the functional roles of the neural components of the projections of the SFO and AP in behavioral, neuroendocrine and physiological controls of water and salt balance. Microtransections, microlesions and aspiration lesions will be used to interrupt specific elements of the neural circuitry and the preparations will be analyzed for specific and general deficits in behavioral and physiological control mechanisms. These preparations will be given individual challenges and their drinking responses followed over the short and long term while monitoring urine output and plasma parameters to assess alterations in internal state. The second major objective is to continue neuroanatomical studies of the neural connectivity of the SFO, AP, and the nucleus of the solitary tract using conjugates of horseradish peroxidase, fluorescent dyes and tritiated amino acids as tracers. Particular attention will be given to the size and location of the afferent sources to the SFO and AP in comparison to the size and destination of their efferent projections. This research will further our understanding of basic mechanisms of thirst and homeostasis and will provide insights into the neural circuitry coordinating behavioral, neuroendocrine and autonomic controls of homeostatic function. It focuses on simple pathways, some between higher forebrain mechanisms and lower brainstem areas receiving direct visceral afferent input. It emphasizes behavioral controls but does not neglect physiological mechanisms to avoid mistaken interpretations of behavioral changes. This multidisciplinary research will better enable understanding of complex health related problems such as hypertension, essential hypernatremia, syndrome of inappropriate antidiuretic hormone secretion and psychogenic polydipsia.